EXCITOTOXINS AND THE NEUROTOXICITY OF AMPHETAMINES

几种安非他明（AMPH），包括甲基安非他明（METH）， 亚甲二氧基甲基安非他明（MDMA）和亚甲二氧基安非他明（MDA） 是一种常见的非法滥用药物。令人担忧的是 AMPH可能对人类中枢神经元造成长期损害。在 实验动物的脑，多巴胺能和/或多巴胺能 神经元因施用AMPH而受损。的类型 单胺能神经元受损取决于注射的类似物以及 使用的动物种类。目前尚不清楚为什么某些类似物发挥 对肾上腺素能神经元的优先效应，或者为什么有一个物种 神经元对AMPH损伤的敏感性的差异。 此外，这些化合物产生神经毒性的机制是 未知AMPH释放多巴胺（DA）和5-羟色胺（5-HT）， 已经假设，由氧化产生的氧衍生产物 这些单胺的氧化可能是有毒物质。我们最近发现 甲基苯丙胺诱导的多巴胺能神经元损伤可以通过 用N-甲基-D-天冬氨酸（NMDA）拮抗剂预处理小鼠 受体，谷氨酸受体的亚型之一。这些发现 表明兴奋性氨基酸（EAA）可能参与了MET诱导的 多巴胺能毒性我们的假设是， METH导致自由基的产生和大量EAA的释放， 导致多巴胺能神经中氧化应激的巨大增加 terminals.这项研究的目的是为了更好地了解 AMPH如何产生毒性，研究EAA的参与， 氧化应激在其毒性，以调查为什么有一个 各种类似物对多巴胺能和多巴胺能的不同作用 神经元，并检查为什么大鼠中的多巴胺能神经元如此之多， 比老鼠更容易受到安非他明的伤害。 生物化学技术和药理学试剂将用于研究 AMPHS的行动。了解AMPH的作用机制 损伤单胺能神经元不仅对 安非他明滥用，但病因不明的疾病，如帕金森氏症 精神分裂症和抑郁症，其中有异常， 多巴胺能和多巴胺能功能。

Several amphetamines (AMPHs) including methamphetamine (METH), methylenedioxymethamphetamine (MDMA) and methylenedioxyamphetamine (MDA) are popular illicit drugs of abuse. Of great concern is the possibility that the AMPHs may cause long-term damage to central neurons in humans. In the brains of experimental animals, dopaminergic and/or serotonergic neurons are damaged by administration of the AMPHs. The type of monoaminergic neuron damaged depends on both the analog injected as well as the species of animal used. It is not clear why certain analogs exert preferential effects on serotonergic neurons or why there is a species difference in the susceptibility of neurons to damage by the AMPHs. Moreover, the mechanisms by which these compounds produce neurotoxicity are unknown. The AMPHs release both dopamine (DA) and serotonin (5HT) and it has been hypothesized that oxygen-derived products resulting from the oxidation of these monoamines may be the toxic species. We recently found that METH-induced damage to dopaminergic neurons can be prevented by pretreatment of mice with antagonists of the N-methyl-D-aspartate (NMDA) receptor, one of the subtypes of the glutamate receptor. These findings indicate that excitatory amino acids (EAAs) may be involved in METH-induced dopaminergic toxicity. Our working hypothesis is that the DA released by METH leads to free radical generation and a large release of EAAs which results in a tremendous increase in oxidative stress in dopaminergic nerve terminals. The aims of this research are to gain a greater understanding of how the AMPHs produce toxicity, to study the involvement of EAAs and oxidative stress in their toxicities, to investigate why there is a differential effect of the various analogs on dopaminergic and serotonergic neurons, and to examine why the serotonergic neurons in the rat are so much more susceptible to amphetamine-induced damage than those in the mouse. Biochemical techniques and pharmacological agents will be used to study the actions of the AMPHS. An understanding of the mechanisms by which the AMPHs damage monoaminergic neurons has important implications not only for amphetamine abuse but for disorders of unknown etiology such as Parkinson's Disease, schizophrenia and depression in which there are abnormalities in dopaminergic and serotonergic function.